Herpes zoster, also known as shingles, results from the reactivation of the virus that causes chickenpox (varicella zoster virus). The virus may spread from one or more ganglia along nerves of an affected segment and infect the corresponding dermatome (an area of skin supplied by one spinal nerve) causing a painful rash. Although the rash usually heals within two to four weeks, some sufferers experience residual nerve pain for months or years, a condition called postherpetic neuralgia.
Throughout the world the incidence rate of herpes zoster every year ranges from 1.2 to 3.4 cases per 1,000 healthy individuals, increasing to 3.9-11.8 per year per 1,000 individuals among those older than 65 years. In early-clinical studies, the bicyclic nucleoside analogue FV-100 has proven to be the most potent antiviral available against this family of viruses.
WO 2001/083501A1, the contents of which are incorporated herein by reference, describes certain nucleoside analogues with potent activity against Varicella Zoster virus (VZV), said nucleoside analogues having general Formula (I):
                wherein:        Ar is an optionally substituted, aromatic ring system, the aromatic ring system comprising one six-membered aromatic ring or two fused six-membered aromatic rings;        R8 and R9 are each independently selected form the group comprising hydrogen, alkyl, cycloalkyl, halogens, amino, alkylamino, dialkylamino, nitro, cyano, alkyloxy, aryloxy, thiol, alkylthiol, arylthiol, aryl;        Q is selected from the group comprising O, S, and CY2, where Y may be the same or different and is selected from H, alkyl and halogens;        X is selected from the group comprising O, NH, S, N-alkyl, (CH2)m, where m is 1 to 10, and CY2 where Y may be the same or different and is selected from hydrogen, alkyl and halogens;        Z is selected from the group comprising O, S, NH, and N-alkyl;        U″ is H and U′ is selected from H and CH2T, or        U′ and U″ are joined so as to form a ring moiety including Q wherein U′-U″ together is respectively selected from the group comprising CTH-CT′T″ and CT′=CT′, so as to provide ring moieties selected from the group comprising        
                                    wherein T is selected from the group comprising OH, H, halogens, O-alkyl, O-acyl, O-aryl, CN, NH2 and N3;                            T′ is selected from the group comprising H and halogens and, where more than one T′ is present, they may be the same or different;                T″ is selected from the group comprising H and halogens; and                                                W is selected from the group comprising H, a phosphate group, and a phosphonate group        and a pharmacologically acceptable salt, derivative, or pro-drug thereof;        with the proviso that when T is OAc, and T′ and T″ are present and are H, Ar is not 4-(2-benzoxazolyl)phenyl.        
Compounds 1 and 2 below are particularly preferred compounds according to WO 2001/083501A1:

WO 2007/129083 A1, the contents of which are incorporated herein by reference, discloses derivatives of Formula (II):
                wherein X is O, S, NH or CH2;        Y is O, S or NH;        Z is O, S or CH2;        R1 is C1-6 alkyl, preferably n-alkyl, e.g., n-pentyl or n-hexyl;        one of R2 and R3 is H, and the other of R3 and R2 is a neutral, non-polar amino acid moiety;        or a pharmaceutically acceptable salt or hydrate thereof.        
Compounds 3 and 4 below are particularly preferred compounds according to WO 2007/129083 A1:

WO 2007/129083 A1 also discloses a method of synthesizing a compound of Formula (II) comprising esterifying a compound of Formula (III):
                with a protected neutral, non-polar amino acid, wherein R1, X, Y and Z are as defined above for Formula (II).        
In the disclosed example for the preparation of Compound 3, the hydroxymethyl nucleoside precursor, Compound 1 is converted to the L-valine final product under conditions employing resin-bound triphenylphosphine and Fmoc-protected valine. Using resin bound reagent facilitates removal of the side product, triphenyl phosphine oxide by filtration, however, the high cost and large volumes required for resin-bound triphenylphosphine makes this method of preparation impractical for scale up purposes. Moreover, due to the poor selectivity between the primary and secondary hydroxyl groups, the bis-valine substituted byproduct can be significant, in which case isolation of sufficiently pure compound FV-100 would require purification by column chromatography.
Methods of preparation that allow production of compounds of Formula (II) in practical yields, are adaptable to large scale preparation, and avoid costly reagents are therefore of value and useful.